Diabeta® product monograph - Sanofi Canada

PRODUCT MONOGRAPH
Pr DIAßETA ®
Glyburide
Manufacturer’s Standard
2.5 and 5 mg Tablets
Oral Hypoglycemic - Sulfonylurea
sanofi-aventis Canada Inc.
2905 Place Louis-R.-Renaud
Laval, Quebec
H7V 0A3
Date of Revision:
March 12, 2013
Submission Control No.: 160736 s-a Version 4.0 dated March 12, 2013
Page 1 of 26

Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION ........................................................... 3
SUMMARY PRODUCT INFORMATION ......................................................................... 3
INDICATIONS AND CLINICAL USE ............................................................................... 3
CONTRAINDICATIONS .................................................................................................... 3
WARNINGS AND PRECAUTIONS ................................................................................... 4
ADVERSE REACTIONS ..................................................................................................... 8
DRUG INTERACTIONS ..................................................................................................... 9
DOSAGE AND ADMINISTRATION ............................................................................... 15
OVERDOSAGE ................................................................................................................. 16
ACTION AND CLINICAL PHARMACOLOGY ............................................................. 17
STORAGE AND STABILITY ........................................................................................... 18
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................. 18
PART II: SCIENTIFIC INFORMATION ................................................................................. 19
PHARMACEUTICAL INFORMATION ........................................................................... 19
CLINICAL TRIALS ........................................................................................................... 20
DETAILED PHARMACOLOGY ...................................................................................... 20
TOXICOLOGY .................................................................................................................. 20
REFERENCES ................................................................................................................... 22
PART III: CONSUMER INFORMATION ................................................................................ 24
Page 2 of 26

PRODUCT MONOGRAPH
Pr DIAßETA ®
Glyburide
Oral Hypoglycemic – Sulfonylurea
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Oral Tablet 2.5 mg, 5 mg Lactose monohydrate
For a complete listing see Dosage Forms,
Composition and Packaging section.
INDICATIONS AND CLINICAL USE
DIAβETA (glyburide) is indicated as an adjunct to proper dietary management, exercise and
weight reduction to lower blood glucose in adult patients with type 2 diabetes whose
hyperglycemia cannot be controlled by diet and exercise alone or when insulin therapy is not
required.
Pediatrics (

Patients with Type 1 diabetes (formerly known as insulin-dependent diabetes
mellitus or IDDM).
Diabetic ketoacidosis with or without coma. This condition should be treated with
insulin.
Diabetic precoma or coma.
During stress conditions such as severe infections, trauma or surgery.
In the presence of liver disease or frank jaundice; or renal impairment.
Patients treated with bosentan.
Pregnancy and lactation.
During pregnancy, no oral antidiabetic agent should be given.
Due to the possible excretion in human milk, the patient should discontinue nursing
or discontinue taking the drug depending on the importance of the drug to the
mother. If glyburide is discontinued, the patient should be transferred to insulin
therapy.
WARNINGS AND PRECAUTIONS
General
Use of DIAβETA must be viewed by both the physician and patient as a treatment in
addition to diet and exercise and not as a substitute for proper dietary management,
exercise and weight reduction or as a convenient mechanism for avoiding dietary
restraint. Furthermore, loss of blood glucose control on diet and exercise alone may be
transient, thus requiring only short-term administration of DIAβETA. As is necessary
during treatment with any blood-glucose-lowering drug, the patient and the physician
must be aware of the risk of hypoglycemia.
In initiating treatment for type 2 diabetes, non-pharmacologic therapy (proper dietary
management, exercise and weight reduction) should be emphasized as the initial form of
treatment. Caloric restriction, weight loss and exercise are essential in the obese diabetic patient.
Proper dietary management and exercise alone may be effective in controlling the blood glucose
and symptoms of hyperglycemia. If non-pharmacologic therapy fails to reduce symptoms and/or
blood glucose, the use of an oral sulfonylurea should be considered.
Patient Selection and Follow-Up
Careful selection of patients is important. It is recommended that response to sulfonylurea be
measured as increased C-peptide. Those patients who do not respond with increased C-peptide
will be less likely to show improvement.
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It is imperative that there be careful ongoing attention to diet, adherence to regular exercise,
reduction of body weight in obese patients, careful adjustment of dosage, instruction of the
patient on hypoglycemic reactions and their control as well as regular, thorough follow-up
examinations. Cardiovascular risk factors should be identified.
The effectiveness of any oral hypoglycemic drug, including DIAβETA, in lowering blood
glucose to a desired level decreases in many patients over a period of time, which may be due to
progression of the severity of the diabetes or to diminished responsiveness to the drug. This
phenomenon, known as secondary failure, is distinctive of primary failure in which the drug is
ineffective in an individual patient when given for the first time.
Patients should therefore be monitored with regular clinical and laboratory evaluations, including
blood glucose and glycosylated hemoglobin (A1 C ) determinations, to determine the minimum
effective dosage and to detect primary failure (inadequate lowering of blood glucose
concentrations at the maximum recommended dosage) or secondary failure (progressive
deterioration in blood sugar control following an initial period of effectiveness). The rate of
primary failure will vary greatly depending upon patient selection and adherence to diet and
exercise. The etiology of secondary failure is multifactorial and may involve progressive β-cell
failure as well as exogenous diabetogenic factors such as obesity, illness, drugs, or tachyphylaxis
to the sulfonylurea.
Cardiovascular
Some literature studies have suggested an association between the use of sulfonylureas and the
risk of cardiovascular adverse events including cardiovascular mortality, since these agents may
potentially impair cardioprotective processes. Although, there is inconsistency in the literature
regarding a definite conclusion for this association, a cautious approach is nevertheless
warranted. All patients on sulfonylureas, particularly high risk patients with cardiovascular
disease, should be closely monitored for cardiovascular complications.
Endocrine and Metabolism
Loss of control of blood glucose
If loss of adequate blood glucose lowering response to sulfonylurea is detected, treatment must
be reassessed.
When a patient stabilized on any diabetic regimen is exposed to stress such as illness during
therapy, fever, trauma, infection, or surgery, a loss of glycemic control may occur. At such times,
it may be necessary to adjust the dosage of DIAβETA or consider discontinuation of DIAβETA
and administration of insulin.
Hypoglycemia
Hypoglycemia, sometimes prolonged and even life-threatening, may occur as a result of the
blood-glucose-lowering action of DIAβETA. Proper patient selection, dosage, and instructions
are important to avoid hypoglycemic episodes.
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Hepatic and/or renal disease, inadequate caloric intake, malnutrition and/or irregular meals,
exercise without adequate caloric supplementation, debility, advanced age, patient noncompliance,
when alcohol is ingested, certain disorders of thyroid function, adrenal or pituitary
insufficiency, excessive DIAβETA dosage, treatment with DIAβETA in the absence of
indication or concurrent use with other agents with blood glucose lowering potential (see DRUG
INTERACTIONS, Drug-Drug Interactions) may be predisposing factors. Oral hypoglycemic
agents should be administered with caution to patients with Addison's disease. If such risk
factors for hypoglycemia are present, it may be necessary to adjust the dosage of DIAβETA or
the entire diabetes therapy. This also applies whenever illness occurs during therapy or the
patient’s life style changes (see DOSAGE and ADMINISTRATION).
The manifestations of hypoglycemia include: flushing or pallor, chilliness, excessive hunger,
trembling, headache, dizziness, nausea, vomiting, restlessness, aggressiveness, depression,
speech disorders, aphasia, sensory and/or visual disturbances, helplessness, lassitude, shallow
respiration or bradycardia. In more severe cases, the clinical symptoms of a stroke or coma
appear. However, symptoms of hypoglycemia are not necessarily as typical as described above
and sulphonylureas may cause insidious development of symptoms mimicking cerebrovascular
insufficiency (e.g. disordered sleep, somnolence, impaired alertness and reactions, confusion,
delirium, cerebral convulsions, paralytic symptoms or loss of consciousness).
Signs of adrenergic counter-regulation to hypoglycemia include: sweating, damp skin, anxiety,
tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmias. However, these
symptoms may be milder or absent in patients who develop hypoglycemia gradually, patients
with autonomic neuropathy, elderly or patients who receive concurrent treatment with
sympatholytic agents (e.g. beta blockers, clonidine, reserpine, guanethidine) (see Drug-Drug
Interactions).
Mild to moderate episodes of hypoglycemia can usually be treated with oral carbohydrates.
Artificial sweeteners are ineffective in controlling hypoglycemia. The symptoms of
hypoglycemia nearly always subside when hypoglycemia is corrected.
Despite initially successful countermeasures, hypoglycemia may recur. Patients must therefore
remain under close observation.
Severe hypoglycemia, which may be prolonged and has occasionally been life-threatening, may
occur and mimics acute CNS disorders. Signs of severe hypoglycemia can include disorientation,
loss of consciousness, and seizures. Severe hypoglycemia, or a protracted episode, which can
only be temporarily controlled by usual amounts of sugar requires in-patient hospital care.
Hematologic
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD)-deficiency with
sulfonylurea agents can lead to hemolytic anemia. Since DIAβETA belongs to the class of
sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a
nonsulfonylurea alternative should be considered.
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Hepatic
The metabolism and excretion of sulfonylureas including DIAβETA may be slowed in patients
with impaired hepatic function (see Monitoring and Laboratory Tests below).
Immune
Persons allergic to other sulfonamide derivatives may develop an allergic reaction to glyburide
(see CONTRAINDICATIONS).
Renal
In patients with renal insufficiency, the initial dosing, dose increments, and maintenance dosage
should be conservative to avoid hypoglycemic reactions.
Special Populations
Pregnant Women:
The use of DIAβETA is contraindicated during pregnancy or for women planning a
pregnancy (see CONTRAINDICATIONS). Recent information suggests that abnormal
blood glucose levels during pregnancy are associated with a higher incidence of
congenital abnormalities. Experts, including the Canadian Diabetes Association and the
Canadian Medical Association recommend that insulin be used during pregnancy to
maintain glucose levels as close to normal as possible.
Nursing women:
The use of DIAβETA is contraindicated in lactating women (see CONTRAINDICATIONS).
Pediatrics:
Safety and effectiveness of DIAβETA has not been established. Use in patients under 18 years of
age is not recommended.
Geriatrics:
Elderly patients with type 2 diabetes are more susceptible to hypoglycemia.
Monitoring and Laboratory Tests
Fasting blood glucose should be monitored periodically to determine therapeutic response.
Glycosylated hemoglobin (HbA 1C ) should also be monitored, usually every 3 to 6 months, to
more precisely assess long-term glycemic control.
Hepatic function should be assessed before initiating therapy and periodically in patients with
impaired hepatic function.
In patients with impaired renal function, blood and urine glucose should be regularly monitored.
Elderly patients (malnourished, with impaired hepatic, renal, or adrenal function) will require
periodic monitoring and special care.
Periodic assessment of cardiovascular, ophthalmic, hematologic, renal and hepatic status is
recommended.
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ADVERSE REACTIONS
Adverse Drug Reaction Overview
The most commonly occurring significant adverse event of sulfonylureas (including
DIAβETA) is hypoglycemia.
The following serious adverse reactions have been reported with DIAβETA:
Cases of severe hypoglycemia that may be prolonged and even life-threatening (see
WARNINGS AND PRECAUTIONS).
Impaired liver function (e.g. cholestasis and jaundice) and hepatitis which can lead to
life-threatening liver failure (isolated cases).
Serious and life-threatening sensitivity reactions including dyspnea, hypotension or shock
(very rare).
Potentially life-threatening cases of thrombocytopenia, leukopenia, agranulocytosis,
pancytopenia, erythrocytopenia, granulocytopenia, hemolytic anemia and aplastic anemia (very
rare).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction
rates observed in the clinical trials may not reflect the rates observed in practice and
should not be compared to the rates in the clinical trials of another drug. Adverse drug
reaction information from clinical trials is useful for identifying drug-related adverse
events and for approximating rates.
Less Common Clinical Trial Adverse Drug Reactions (

suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of
ADH and/or increased release of ADH.
Gastrointestinal:
Nausea, epigastric fullness and heartburn are common reactions. Vomiting, diarrhea, and
abdominal pain have also been reported. These tend to be dose related and may disappear
when dosage is reduced.
Hematologic:
Potentially life-threatening changes in the blood picture may occur. Rare cases of mild to severe
thrombocytopenia which can manifest itself as purpura have been reported. Leukopenia,
agranulocytosis, pancytopenia (which may be due to myelosuppression), erythrocytopenia,
granulocytopenia, hemolytic anemia and aplastic anemia have been observed very rarely with
DIAβETA therapy. These reactions may be reversible following discontinuation of the
sulfonylurea antidiabetic agent.
Sensitivity/Resistance:
Allergic and pseudoallergic skin reactions such as pruritus, erythema, rashes, urticaria,
morbilliform or maculopapular eruptions have been reported in a number of patients. These may
subside on continued use of DIAβETA, but if they persist the drug should be discontinued. Mild
reactions such as urticaria may very rarely develop into serious and life-threatening reactions
including dyspnea, hypotension or shock. In the event of urticaria, a physician must therefore be
notified immediately. Porphyria cutanea tarda and photosensitivity reactions have been
associated with the use of oral hypoglycemic drugs. Allergic vasculitis has been observed very
rarely in patients receiving DIAβETA and in some circumstances may be life-threatening.
Cross-sensitivity to sulfonamides or their derivatives may occur in patients treated with oral
sulfonylurea hypoglycemic agents (see CONTRAINDICATIONS).
Other:
Transient visual disturbances may occur at the commencement of treatment due to fluctuations in
blood glucose levels.
DRUG INTERACTIONS
Overview
Weakening of the blood-glucose-lowering effect and, thus, raised blood glucose levels or
potentiation of the blood-glucose lowering effect and thus hypoglycemia may occur when taking
other drugs.
DIAβETA is mainly metabolized by CYP2C9 and by CYP3A4. This should be taken into
account when DIAβETA is co-administered with inducers or inhibitors of CYP2C9 and
CYP3A4. Genetic polymorphisms of CYP2C9 may decrease oral clearance of DIABETA (see
ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Page 9 of 26

Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering
action of DIAβETA in an unpredictable fashion. Intolerance to alcohol (disulfiram-like reaction:
flushing, sensation of warmth, giddiness, nausea, and occasionally tachycardia) may occur in
patients treated with oral hypoglycemic drugs. These reactions can be prevented by avoiding the
use of alcohol.
Page 10 of 26

Drug-Drug Interactions
Patients who receive or discontinue certain medications while undergoing treatment with
DIAβETA may experience changes in blood glucose control.
Table 1. Drugs that may potentiate the hypoglycemic action
Proper name Reference Effect Clinical comment
ACE-inhibitors T The hypoglycemic action of When these drugs are
Anabolic steroids and T
sulfonylureas may be administered to a patient
androgens
potentiated.
receiving DIAβETA, the patient
Beta-blockers T
should be observed closely for
Chloramphenicol T
hypoglycemia. When these drugs
Clarithromycin C
are withdrawn from a patient
Coumarin derivatives T
receiving DIAβETA, the patient
Cyclophosphamide T
should be observed closely for
Disopyramide T
loss of glycemic control.
Fenfluramine T
Fibrates
T
Fluconazole
T
Fluoxetine
T
Guanethidine T
Ifosfamide
T
Miconazole
T
Monoamine oxidase T
inhibitors
Nonsteroidal antiinflammatory
T
drugs
Oxyphenbutazone T
Para-aminosalicylic T
acid
Pentoxifylline (high T
dose parenteral)
Phenylbutazone T
Probenecid
T
Propranolol
T
Quinolones
T
Salicylates
T
Sulfonamides (e.g T
sulphaphenazole)
Sulphinpyrazone T
Sympatholytic agents T
(e.g. beta-blockers,
guanethidine)
Tetracyclines T
Tuberculostatics T
Page 11 of 26

Table 2. Drugs that may produce hyperglycemia and lead to loss of blood sugar control
Reference Effect
Proper name
Acetazolamide T These drugs tend to produce
Barbiturates
T
hyperglycemia and may lead
Corticosteroids T
to loss of blood sugar control
Diazoxide
T
Diuretics (thiazides, T
furosemide)
Epinephrine and other T
sympathomimetic
agents
Estrogen and
T
progestogen
Glucagon
T
Clinical comment
When these drugs are
administered to a patient
receiving DIAβETA, the patient
should be observed closely for
loss of glycemic control. When
these drugs are withdrawn from a
patient receiving DIAβETA, the
patient should be observed
closely for hypoglycemia.
Isoniazid
Laxatives (after
protracted use)
Nicotinic acid (in
pharmacologic doses)
Phenothiazines
Phenytoin
Rifampicin
Thyroid products
T
T
T
T
T
T
T
Table 3. Other drugs that may interact with DIAβETA
Proper name Reference Effect Clinical comment
Beta-blockers
T
Concurrent use with
(see also table1)
DIAβETA may lead to either
a potentiation or an
attenuation of the bloodglucose-lowering
effect
The signs of adrenergic
counter-regulation to
hypoglycemia may be
reduced or absent in case of
concomitant use with
DIAβETA.
Bosentan C An increased incidence of
elevated liver enzymes was
observed in patients
receiving DIAβETA
concomitantly with bosentan.
Both DIAβETA and
This combination should not be
used.
Page 12 of 26

osentan inhibit the bile salt
export pump, leading to
intracellular accumulation of
cytotoxic bile salts.
Barbiturates T Prolonged barbiturate action To be used cautiously in
patients receiving an oral
hypoglycemic agent.
Clonidine T Concurrent use with
DIAβETA may lead to either
a potentiation or an
attenuation of the bloodglucose-lowering
effect
The signs of adrenergic
counter-regulation to
hypoglycemia may be
reduced or absent in case of
concomitant use with
DIAβETA.
Colesevelam C Colesevelam binds to
DIAβETA and reduces
DIAβETA absorption from
the gastrointestinal track
Coumarin derivatives T DIAβETA may potentiate or
weaken the effects of
coumarin derivatives.
Cyclosporine C DIAβETA may increase
cyclosporine plasma level,
with potentially increased
toxicity.
Drugs containing
alcohol
(see also Drug-
Lifestyle
Interactions
below)
C
Both acute and chronic
alcohol intake may potentiate
or weaken the bloodglucose-lowering
action of
DIAβETA in an
unpredictable fashion.
Guanethidine T The signs of adrenergic
counter-regulation to
hypoglycemia may be
reduced or absent in case of
concomitant use with
No interaction was observed
when DIAβETA was taken at
least 4 hours before
colesevelam. Therefore,
DIAβETA should be
administered at least 4 hours
prior to colesevelam.
Monitoring and dosage
adjustment of cyclosporin are
recommended when both drug
are coadministered.
Intolerance to alcohol
(disulfiram-like reaction;
flushing, sensation of warmth,
giddiness, nausea, and
occasionally tachycardia) may
occur in patients treated with
oral hypoglycemic drugs.
Caution should be exercised
with the concomitant use of
alcohol-containing drugs.
Page 13 of 26

DIAβETA.
H 2 -receptor antagonists T Concurrent use with
DIAβETA may lead to either
a potentiation or an
attenuation of the bloodglucose-lowering
effect
Reserpine T Concurrent use with
DIAβETA may lead to either
a potentiation or an
attenuation of the bloodglucose-lowering
effect
Sympatholytic drugs
(such as beta-blockers,
clonidine, guanethidine,
and reserpine)
T
Legend: C = case study; CT = Clinical Trial; T = Theoretical
The signs of adrenergic
counter-regulation to
hypoglycemia may be
reduced or absent in case of
concomitant use with
DIAβETA
The signs of adrenergic
counter-regulation to
hypoglycemia may be
reduced or absent in case of
concomitant use with
DIAβETA.
In addition, the hypoglycemic action of sulfonylureas is potentiated when used with insulin and
other oral antidiabetics, which is not indicated.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Tests Interactions
Interactions with laboratory tests have not been established.
Drug-Lifestyle Interactions
Alertness and reactions may be impaired due to hypo- or hyperglycemia, especially when
beginning or after altering treatment, or when DIAβETA is not taken regularly. This may,
for example, affect the ability to drive or to operate machinery.
Page 14 of 26

DOSAGE AND ADMINISTRATION
Dosing Considerations
In diabetic subjects, there is no fixed dosage regimen for management of blood glucose levels.
Individual determination of the minimum dose that will lower the blood glucose adequately
should be made, aiming for glycemic targets as close to normal as possible and, in most people,
as early as possible.
Over a period of time, patients may become progressively less responsive to therapy with oral
hypoglycemic agents because of deterioration of their diabetic state. Patients should therefore be
monitored with regular clinical and laboratory evaluations, including blood glucose and
glycosylated hemoglobin (A1 C ) measurements, to determine the minimum effective dosage and
to detect primary failure or secondary failure (see WARNINGS AND PRECAUTIONS).
Adjustment of glyburide dosage should be considered whenever factors predisposing the patient
to the development of hypo- or hyperglycemia, such as illness, weight or life-style changes, are
present (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE
REACTIONS). As an improvement in control of diabetes is, in itself, associated with higher
insulin sensitivity, DIAβETA requirements may fall as treatment proceeds. To avoid
hypoglycemia, timely dose reduction or cessation of DIAβETA therapy must therefore be
considered.
Based on published literature, genetic polymorphisms of CYP2C9 may be associated with an
increased response to DIAβETA. A lower dose regimen in poor metaboliser (CYP2C9*3 variant)
should be considered, however an appropriate dose regimen for this patient population has not
been established in clinical outcome trials (see ACTION AND CLINICAL PHARMACOLOGY,
Pharmacokinetics).
Recommended Dose and Dosage Adjustment
Newly-Diagnosed Diabetics
The initial dose is 5 mg daily (2.5 mg in patients over 60 years of age) administered with
breakfast or a first meal and should be continued for 5 to 7 days. Depending on the response, the
dosage should then be either increased or decreased by steps of 2.5 mg. The maximum daily dose
of DIAβETA is 20 mg (higher doses normally have no additional effect on control of metabolic
state). Occasionally, control is maintained with 2.5 mg daily. The majority of cases can be
controlled by 5 to 10 mg (1 to 2 tablets) daily given as a single dose during or immediately after
breakfast. Patients who eat only a light breakfast should defer the first dose of the day until
lunchtime. If more than 10 mg (2 tablets) daily is required, the excess should be taken with the
evening meal. It is very important not to skip meals after the tablets have been taken.
Changeover from Other Oral Hypoglycemic Agents
There is no exact dosage relationship between DIAβETA and other oral antidiabetic agents.
Discontinue previous oral medication and start DIAβETA 5 mg daily (2.5 mg in patients over 60
Page 15 of 26

years of age). This also applies to patients changed over from the maximum dose of other oral
antidiabetic medication. Determine maintenance dosage as in newly diagnosed diabetics.
Consideration must be given to the potency and duration of action of the previous antidiabetic
agent. A break from medication may be required to avoid any summation of effects entailing a
risk of hypoglycemia.
Changeover from Insulin
If a change from insulin to DIAβETA is contemplated in a patient with stable, mild, Type 2
diabetes, treatment with insulin should be discontinued for a period of two or three days to
determine whether any therapy other than dietary regulation and exercise is needed. During this
insulin-free interval, the patient's urine should be tested at least three times daily for glucose and
ketone-bodies, and the results monitored carefully by a physician. The appearance of significant
ketonuria accompanied by glucosuria within 12 - 24 hours after the withdrawal of insulin
strongly suggests that the patient is ketosis-prone and precludes the change from insulin to
DIAβETA.
Missed Dose
The missed dose should be taken as soon as possible, unless it is almost time for the next dose.
Mistakes, e.g. forgetting to take a dose, must never be corrected by subsequently taking a larger
dose.
Measures for dealing with such mistakes (in particular forgetting a dose or skipping a meal) or in
the event a dose cannot be taken at the prescribed time must be discussed and agreed between
physician and patient beforehand.
If it is discovered that too high a dose or an extra dose of DIAβETA has been taken, a physician
must be notified immediately.
OVERDOSAGE
Overdosage of sulfonylureas, including DIAβETA, can produce hypoglycemia. Mild
hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated
with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should
continue until the physician is assured that the patient is out of danger. Severe hypoglycemic
reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute
medical emergencies requiring immediate hospitalization. In case of overdosage, current medical
intervention for the treatment of hypoglycemia should be followed according to the condition of
the patient. Patients should be closely monitored for a minimum of 24 hours, because
hypoglycemia may recur after apparent clinical recovery.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Page 16 of 26

ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
DIAβETA appears to lower the blood glucose acutely by stimulating the release of insulin from
the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The
mechanism by which DIAβETA lowers blood glucose during long-term administration has not
been clearly established.
With chronic administration in Type II diabetic patients, the blood glucose lowering effect
persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic
effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. In
addition to its blood glucose lowering actions, DIAβETA produces a mild diuresis by
enhancement of renal free water clearance. Clinical experience to date indicates an extremely
low incidence of disulfiram-like reactions in patients while taking DIAβETA.
Pharmacokinetics
Single-dose studies with DIAβETA in normal subjects demonstrate significant absorption within
one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours.
Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve,
increase in proportion to corresponding increases in dose. Multiple-dose studies with DIAβETA
in diabetic patients demonstrate drug level concentration-time curves similar to single dose
studies, indicating no build-up of drug in tissue depots. The decrease of glyburide in the serum of
normal healthy individuals is biphasic, the terminal half-life being about 10 hours. In single-dose
studies in fasting normal subjects, the degree and duration of blood glucose lowering is
proportional to the dose administered and to the area under the drug level concentration-time
curve. The blood glucose lowering effect persists for 24 hours following single morning doses in
non-fasting diabetic patients. Under conditions of repeated administration in diabetic patients,
however, there is no reliable correlation between blood drug levels and fasting blood glucose
levels. A one-year study of diabetic patients treated with DIAβETA showed no reliable
correlation between administered dose and serum drug level.
DIAβETA is eliminated by extensive metabolism in liver. Currently available information from
published in vitro and in vivo pharmacokinetics studies suggest that DIAβETA is mainly
metabolized by CYP2C9 and by CYP3A4. This should be taken into account when DIAβETA is
coadministered with inducers or inhibitors of CYP2C9 and CYP3A4 to avoid potential drug-drug
interactions (see DRUG INTERACTIONS). Genetic polymorphisms may reduce the metabolic
capability of 2C9. Some clinical studies in a limited number of subjects have shown that genetic
polymorphisms of CYP2C9 affect the pharmacokinetics of DIAβETA and that the carriers of
CYP2C9*3 variant (3-8.5% of Caucasians) have lower (30-57%) oral clearance and 1 to 3-fold
higher exposure (AUC (0-∞) ) of DIAβETA. Individuals expressing this variant genotype may
therefore be predisposed to have an increased response to DIABETA. Moreover, the CYP2C9
*3/*3 and *2/*3 genotypes may have an increased risk of hypoglycemia.
The major metabolite of DIAβETA is the 4-trans-hydroxy derivative. A second metabolite, the 3-
cis-hydroxy derivative, also occurs. These metabolites contribute no significant hypoglycemic
Page 17 of 26

action since they are only weakly active (1/400th and 1/40th, respectively, as glyburide) in
rabbits.
DIAβETA is excreted as metabolites in the bile and urine, approximately 50% by each route.
This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are
excreted primarily in the urine.
Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding
sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding
exhibited by DIAβETA is predominantly non-ionic, whereas that of other sulfonylureas
(chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as
phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum
proteins to a far greater extent than the non-ionic binding DIAβETA. It has not been shown that
this difference in protein binding will result in fewer drug-drug interactions with DIAβETA in
clinical use.
STORAGE AND STABILITY
DIAβETA should be stored between 15 and 30ºC, and not beyond the expiry date indicated on
the package.
DOSAGE FORMS, COMPOSITION AND PACKAGING
DIAβETA (glyburide) 2.5 mg contains 2.5 mg glyburide. DIAβETA (glyburide) 5.0 mg contains
5.0 mg glyburide. Each tablet also contains as non-medicinal ingredients: colloidal anhydrous
silica, lactose monohydrate, magnesium stearate, starch (corn starch and pre-gelatinized corn
starch) and talc.
DIAβETA (glyburide) 2.5 mg tablets are compressed white, flat round beveled tablets with code
letter "LB" above and "G" below the breakline on one side and plain on the other. Available in
cartons of 30 (2 x 15 blister pack).
DIAβETA (glyburide) 5.0 mg tablets are white, biplane, oblong tablets with a score line on both
sides, "LDI" is engraved on each side of the score-line and inverted. The other face is plain.
Available in cartons of 30 (2 x 15 blister pack) or HDPE bottles of 300 tablets.
Page 18 of 26

PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name:
Chemical name:
Molecular formula:
Glyburide (as per USP)¸ Glibenclamide (as per Ph. Eur.)
1-[[4-[2-[(5-Chloro-2-
methoxybenzoyl)amino]ethyl]phenyl]sulphonyl]-3-cyclohexylurea
C 23 H 28 ClN 3 0 5 S
Molecular mass: 494
Structural formula:
Physicochemical properties:
White or almost white, crystalline powder. Practically
insoluble in water, sparingly soluble in methylene chloride,
slightly soluble in alcohol and in methanol, with a melting
range of 169 – 174 °C.
Page 19 of 26

CLINICAL TRIALS
No clinical data available.
DETAILED PHARMACOLOGY
Animal
In the isolated, perfused rat pancreas, glyburide produced a sustained rise in insulin output. In the
presence of 0.5 mcg/mL of glyburide, isolated rat pancreatic islets released insulin continuously 3 .
When isolated pieces of rat pancreas were repeatedly exposed to glucose or glyburide for brief
periods of time at intervals of 30 minutes, they consistently released insulin 3 . In the presence of
300 mg% of glucose, glyburide (2.5 mcg/min) increased effectively insulin output from isolated
rat pancreas 3,4 .
Sirek et al. 13 found that the beta adrenergic blocker propranolol inhibits sulfonylurea-stimulated
insulin secretion in the dog and that the hypoglycemia produced by glyburide in the presence of
propranolol could be the result of extra-pancreatic effects.
TOXICOLOGY
The LD 50 for white mice, rats and guinea pigs was found to be more than 15 g/kg body weight
and for rabbits and beagles, more than 10 g/kg body weight when glyburide is given orally. The
LD 50 in rats following intraperitoneal injection is 6.3 to 8.4 g/kg body weight.
Long-term feeding experiments were carried out in rats and dogs over the course of one year.
Rats were given glyburide in their food in doses of approximately 0.2, 1.0 and 5.0 mg/kg body
weight daily. The highest dose is equivalent to 350 times the minimal hypoglycemic dose in
man. Organ function tests were carried out continuously. Hematological examination, blood
sugar tests and urinary analyses were performed every three months. None of the rats showed
any abnormal findings in the function tests or the blood and urine studies. Subsequent
post-mortem examination revealed no macroscopic or histological changes attributable to a toxic
effect of glyburide.
Dogs were given glyburide by mouth at dose levels of 0.4, 2.0 and 10.0 mg/kg body weight
daily. The highest dose is equivalent to 650 times the minimal effective hypoglycemic dose in
man. Regular checks of blood cell counts, blood glucose, urine, electrolytes, electrophoresis,
BUN and serum enzyme levels (GPT, GOT, LDH, AP) showed no abnormalities. All the animals
behaved normally during the period of the experiment. There was no vomiting or diarrhea, and
their weights remained unchanged. Subsequent post-mortem examination and histological
investigations showed no abnormality.
Teratological tests were carried out in rats and rabbits. Rats were given 0.2, 20 and 2,000 mg/kg
body weight of glyburide from day 7 to 16 of gestation. For rabbits the doses were 0.035, 3.5 and
350 mg/kg given from day 7 to 17 of gestation in a starch suspension by gastric tube.
Page 20 of 26

Examination of the intact fetuses, followed by examination of transverse sections and of the
stained skeleton, showed no evidence of teratogenic action.
Page 21 of 26

REFERENCES
1. Blant L, Fabre J, Zahno GR. Comparison of the pharmacokinetics of Glipizide in Glipizide
in Glibenclamide in man. Europ J Clin Pharmacol 1975;9:63-69.
2. Falko JM, Osei K. Combination insulin/glyburide therapy in Type II diabetes mellitus.
Effects on lipoprotein metabolism and glucoregulation. The American Journal of
Medicine. 1985 September 20;79 Suppl 3B:92-101.
3. Fucella ML, Tamassia V, Valzelli G. Metabolism and kinetics of the hypoglycemic agent
Glipizide in man - comparison with Glibenclamide. J Clin Pharmacol. 1973;13:68-75.
4. Fussgaenger RD, Goberna R, Hinz M, Jaros P, Karsten C, Pfeiffer EF, Raptis S.
Comparative studies of the dynamics of insulin secretion following HB 419 and
tolbutamide of the perfused isolated rat pancreas and the perfused isolated pieces and islets
of rat pancreas. Hormone and Metabolic Research. 1969;1 Suppl:34.
5. Grodsky GM, Curry D, Landahl H, Bennet L. Further studies on the dynamic aspects of
insulin release in-vitro with evidence of a two-compartmental storage system. Acta
Diabetological Latina 1969;6 Suppl 1:554.
6. Hajdu P, Kohler KF, Schmidt FH, Spingher H. Physikalisch-chemische und analytische
Unter suchungen an HB 419. Arzneim Forsch 1969;19(suppl):1381-1386.
7. Hirn S, Konigstein RP. HB 419, ein neues orales Antidiabetikum und sein Anwendung in
hohen Alter. Weiner Medizinische Wochenschrift 1969;111:632.
8. Karlander SG, Gutniak MKM, Efendic S. Effects of combination therapy with glyburide
and insulin on serum lipid levels in NIDDM patients with secondary sulfonylurea failure.
Diabetes Care. 1991 November;14(11):963-967
9. Mariani MM. The action of sulfonylureas on the insulin secretion of the perfused rat
pancreas. Acta Diabetologica Latina 1969;6 Suppl 1:256.
10. Morris AD, Boyle D, McMahon AD, Pearce H, Evans J, Newton RW. ACE inhibitor use is
associated with hospitalization for severe hypoglycemia in patients with diabetes. Diabetes
Care. 1997 Sept; 20(9): 1363-7.
11. Raptis S, Rau RM, Schroeder KE, Faulhaber JD, Pfeiffer EF. Comparative study of insulin
secretion following repeated administration of Glucose, Tolbutamide and Glibenclamide
(HB 419) in diabetic and non-diabetic human subjects. Hormone and Metabolic Research
1969;1 Suppl:65.
12. Reich A, Abraira C, Lawrence AM. Combined Glyburide and insulin therapy in Type II
diabetes. Diabetes Research 1987; 6: 99-104
Page 22 of 26

13. Rupp W, Christ OE, Fuelberth W. Studies on the bioavailability of Glibenclamide. Arzneim
Forsch 1972;22:47.
14. Rupp W. Bioequivalence study - Glyburide. (Dossier technique, Hoechst Pharmaceuticals,
Département médical, Montréal, Qué.).
15. Rupp W. Dose-response study of the Hoechst formulation of Glyburide. (Dossier
technique, Hoechst Pharmaceuticals, Département médical, Montréal, Qué.).
16. Schulz E, Schmidt FH. Uber den Einfluss von sulfaphenazol, phenylbutazon und
phenprocumarol auf die Elimination von Glibenclamid beim Menschen. Verhandlunen
deutsche Geselschaft fur innue Medizin 1970;76:435.
17. Sirek OV, Sirek A et Policova Z. Inhibition of sulphonylurea-stimulated insulin in secretion
by beta adrenergic blockade. Diabetologia 1975;II(4):269.
18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complications
in patients with Type 2 diabetes (UKPDS 33). The Lancet. 1998;352:837-853.
Page 23 of 26

IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
DIAβETA ®
Glyburide Tablets
This leaflet is part III of a three-part “Product Monograph"
published when DIAβETA was approved for sale in Canada
and is designed specifically for Consumers. This leaflet is a
summary and will not tell you everything about DIAβETA.
Contact your doctor or pharmacist if you have any
questions about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
DIAβETA (glyburide) is used as an adjunct to proper diet,
exercise and weight reduction to lower blood glucose in adult
patients with type 2 diabetes mellitus.
What it does:
DIAβETA lowers blood sugar by stimulating the pancreas to
secrete insulin. The pancreas must produce insulin for this
medication to work.
People with type 2 diabetes are not able to make enough insulin
or respond normally to the insulin their bodies make. When this
happens, sugar (glucose) builds up in the blood. This can lead to
serious medical problems including kidney damage,
amputations, and blindness. Diabetes is also closely linked to
heart disease. The main goal of treating diabetes is to lower
your blood sugar to a normal level and by doing so can prevent
long term complications.
In addition to taking DIAβETA, you should continue to exercise
and follow the diet recommended for you by your doctor.
When it should not be used:
Do not take DIAβETA
If you have Type 1 diabetes.
If you have known hypersensitivity or allergy to this drug,
any sulfonylurea or sulfonamides, or to any ingredient in
the formulation or component of the container.
If you have diabetic ketoacidosis (an emergency condition
with high blood glucose levels, a lack of insulin and an
accumulation of ketones (chemicals) in the blood and
urine). This condition should be treated with insulin.
Diabetic precoma or coma.
During stress conditions such as severe infections, trauma
or surgery.
In the presence of liver disease or frank jaundice; or kidney
disease.
If you are being treated with bosentan.
If you are pregnant or breastfeeding.
What the medicinal ingredient is:
The medicinal ingredient for DIAβETA is glyburide.
What the important nonmedicinal ingredients are:
DIAβETA tablets contain the following non-medicinal
ingredients: colloidal anhydrous silica, lactose monohydrate,
magnesium stearate, starch (corn starch and pre-gelatinized
corn starch) and talc.
What dosage forms it comes in:
Tablets. Each tablet contains 2.5 mg or 5.0 mg glyburide.
WARNINGS AND PRECAUTIONS
Proper diet, exercise and weight reduction are important to
help you control your diabetes.
Your blood glucose may change in some situations, for
example if you are stressed or suffering from other illnesses
(e.g. infections). At such times, your doctor may need to
modify your dose.
DIAβETA may cause low blood sugar (hypoglycemia),
especially if you miss a meal, exercise for a long time, drink
alcohol or use another antidiabetic medication with
DIAβETA.
If your blood sugar gets too low, you may feel shaky, weak,
drowsy, confused, or very hungry. You may sweat or have
blurred vision, abnormal heartbeats, trouble concentrating,
or a headache that doesn't go away. Signs of severe
hypoglycemia can include disorientation, loss of
consciousness, and seizures.
You should ask your doctor, pharmacist or diabetes educator
about symptoms of low blood sugar and what to do if you
experience these symptoms. Teach your friends, co-workers,
or family members what they can do to help you if you have
low blood sugar.
You should also test your blood sugar as instructed by your
doctor.
Before you use DIAβETA talk to your doctor or pharmacist
if:
You have or have had liver, kidney, or heart disease;
You are pregnant or planning to get pregnant;
You are breast-feeding.
You have a blood disease called G6PD-deficiency
anemia
DIAβETA is not recommended for use in children under 18
years of age.
Page 24 of 26

IMPORTANT: PLEASE READ
Driving and Operating Machinery:
Alertness and reactions may be impaired due to low or high
blood sugar (hypo- or hyperglycemia), especially when
beginning or after changing treatment or when DIAβETA is not
taken regularly. This may affect your ability to drive or to
operate machinery.
INTERACTIONS WITH THIS MEDICATION
Ask your doctor or pharmacist before taking any other
medicine, including over-the-counter products.
Drugs that can interact with DIAβETA include: diuretics (water
pills), corticosteroids (such as prednisone), ACE inhibitors (a
drug used to treat high blood pressure (hypertension)), birth
control pills, and some kinds of cold and allergy drugs.
Avoid drinking alcohol while you are taking DIAβETA.
PROPER USE OF THIS MEDICATION
Usual dose:
Take DIAβETA exactly as prescribed by your doctor.
The usual dose is 2.5 to 10 mg daily. Maximum daily dose is 20
mg.
A dose of more than 10 mg should be taken in two divided
doses.
Tablets should be taken during or immediately after meals.
Overdose:
Overdosage with this medication may result in hypoglycemia.
In case of drug overdose, contact a health professional,
hospital emergency department or regional Poison Control
Centre immediately, even if there are no symptoms.
Missed Dose:
If you forget to take DIAβETA tablets, do not take a double
dose to make up for forgotten individual doses.
Discuss with your healthcare for dealing with such mistakes (in
particular forgetting a dose or skipping a meal) or in the event a
dose cannot be taken at the prescribed time.
SIDE EFFECTS AND WHAT TO DO ABOUT
THEM
Side effects:
As with any type of medication, DIAβETA is associated with
some side effects.
The most common side effect of DIAβETA is low blood
sugar (hypoglycemia). Please see the WARNINGS and
PRECAUTIONS section above.
The following side effects have been observed with
DIAβETA use: nausea, heartburn, feeling “full”, vomiting,
diarrhea and abdominal pain.
Allergic skin reactions (itchiness, rash, eruption) have been
reported in a number of patients. An increased sensibility to
light has been associated with the use of oral antidiabetic
drugs.
Transient visual disturbances may occur at the beginning of
the treatment due to variations in level of blood sugar.
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
Symptom/
Effect
Common
Uncommon
Rare
Very rare
Low blood
sugar
(hypoglycemia)
Skin reactions
(itchiness, rash,
eruption)
Blood
disorders
(unusual
bruising or
bleeding)
Liver problem
(yellowing of
the eyes or
skin)
Allergic
reaction
(difficult
breathing,
decreased
blood pressure)
Talk with
your doctor
or pharmacist
Only
if
severe
√
In
all
cases
√
√
Stop taking
DIAβETA
and call
your doctor
or
pharmacist
This is not a complete list of side effects. For any
unexpected effects while taking DIAβETA, contact your
doctor or pharmacist.
√
√
Page 25 of 26

IMPORTANT: PLEASE READ
HOW TO STORE IT
DIAβETA should be stored between 15-30°C, and not beyond
the expiry date indicated on the package.
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions
associated with the use of health products to the
Canada Vigilance Program by one of the following 3
ways:
Report online at:
www.healthcanada.gc.ca/medeffect
Call toll-free at 1-866-234-2345
Complete a Canada Vigilance Reporting Form
and:
- Fax toll-free to 1-866-678-6789, or
- Mail to:
Canada Vigilance Program
Health Canada
Postal Locator 0701E
Ottawa, ON K1A 0K9
Postage paid labels, Canada Vigilance Reporting
Form and the adverse reaction reporting guidelines
are available on the MedEffect Canada Web site at
www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to the
management of side effects, contact your health
professional. The Canada Vigilance Program does
not provide medical advice.
MORE INFORMATION
This document plus the full product monograph, prepared for
health professionals can be found by contacting the sponsor,
sanofi-aventis Canada Inc., at: at: 1-800-265-7927 or at
www.sanofi.ca
This leaflet was prepared by sanofi-aventis Canada Inc.
Last revised: March 12, 2013
Page 26 of 26